Human Pharmaceuticals in the Environment: Current and Future Perspectives pot

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Emerging Topics in Ecotoxicology
Principles, Approaches and Perspectives
Volume 4
Series Editor
Lee R. Shugart
L.R. Shugart and Associates, Oak Ridge, TN, USA

Bryan W. Brooks

Duane B. Huggett
Editors
Human Pharmaceuticals
in the Environment
Current and Future Perspectives
Editors
Bryan W. Brooks
Baylor University
Waco, Texas, USA
Duane B. Huggett
University of North Texas
Denton, Texas, USA
ISSN 1868-1344 ISSN 1868-1352 (electronic)
ISBN 978-1-4614-3419-1 ISBN 978-1-4614-3473-3 (eBook)
DOI 10.1007/978-1-4614-3473-3
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v
Perspectives on Human Pharmaceuticals in the Environment 1
Bryan W. Brooks, Jason P. Berninger, Alejandro J. Ramirez,
and Duane B. Huggett
Environmental Risk Assessment for Human Pharmaceuticals:
The Current State of International Regulations 17
Jürg Oliver Straub and Thomas H. Hutchinson
Regulation of Pharmaceuticals in the Environment: The USA 49
Emily A. McVey
Environmental Fate of Human Pharmaceuticals 63
Alistair B.A. Boxall and Jon F. Ericson
Environmental Comparative Pharmacology: Theory
and Application 85
Lina Gunnarsson, Erik Kristiansson, and D.G. Joakim Larsson
A Look Backwards at Environmental Risk Assessment:
An Approach to Reconstructing Ecological Exposures 109
David Lattier, James M. Lazorchak, Florence Fulk, and Mitchell Kostich
Considerations and Criteria for the Incorporation of
Mechanistic Sublethal Endpoints into Environmental
Risk Assessment for Biologically Active Compounds 139
Richard A. Brain and Bryan W. Brooks

Human Health Risk Assessment for Pharmaceuticals in the
Environment: Existing Practice, Uncertainty, and Future Directions 167
E. Spencer Williams and Bryan W. Brooks
Contents
vi
Contents
Wastewater and Drinking Water Treatment Technologies 225
Daniel Gerrity and Shane Snyder
Pharmaceutical Take Back Programs 257
Kati I. Stoddard and Duane B. Huggett
Appendix A. Take Back Program Case Studies 287
Index 297
vii
Jason P. Berninger Department of Environmental Science , Center for Reservoir
and Aquatic Systems Research, Institute of Biomedical Studies, Baylor University ,
Waco , TX 76798 , USA
Of fi ce of Research and Development, National Health and Environmental Effects
Research Laboratory , U.S. Environmental Protection Agency , Duluth , MN 55804 , USA
Alistair B. A. Boxall Environment Department , University of York , Heslington ,
York YO10 5DD , UK
Richard A. Brain Ecological Risk Assessment , Syngenta Crop Protection LLC ,
Greensboro , NC 27409 , USA
Bryan W. Brooks Department of Environmental Science , Center for Reservoir
and Aquatic Systems Research, Institute of Biomedical Studies, Baylor University ,
Waco , TX 76798 , USA
Jon F. Ericson P fi zer Global Research and Development, Worldwide PDM,
Environmental Sciences , MS: 8118A-2026 , Groton , CT 06340 , USA
Florence Fulk National Exposure Research Laboratory, Ecological Exposure
Research Division , US Environmental Protection Agency, Of fi ce of Research and
Development , Cincinnati , OH 45268 , USA

Daniel Gerrity Water Quality Research and Development Center , Southern
Nevada Water Authority, River Mountain Water Treatment Facility , Henderson ,
NV 89015 , USA
Lina Gunnarsson Department of Neuroscience and Physiology, Institute of
Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg ,
405 30 Göteborg , Sweden
Duane B. Huggett Department of Biological Sciences , University of North Texas ,
Denton , TX 76203 , USA
Contributors
viii
Contributors
Thomas H. Hutchinson CEFAS Weymouth Laboratory, Centre for Environment,
Fisheries and Aquaculture Sciences , Weymouth , Dorset DT4 8UB , UK
Mitchell Kostich National Exposure Research Laboratory, Ecological Exposure
Research Division, US Environmental Protection Agency, Of fi ce of Research and
Development , Cincinnati , OH 45268 , USA
Erik Kristiansson
Department of Neuroscience and Physiology, Institute of
Neuroscience and Physiology , The Sahlgrenska Academy, University of Gothenburg ,
405 30 Göteborg , Sweden
Department of Zoology, University of Gothenburg, 405 30 Göteborg, Sweden
D.G. Joakim Larsson Department of Neuroscience and Physiology, Institute of
Neuroscience and Physiology , The Sahlgrenska Academy, University of Gothenburg ,
405 30 Göteborg , Sweden
David Lattier National Exposure Research Laboratory, Ecological Exposure
Research Division, US Environmental Protection Agency, Of fi ce of Research and
Development , Cincinnati , OH 45268 , USA
James M. Lazorchak National Exposure Research Laboratory, Ecological
Exposure Research Division, US Environmental Protection Agency, Of fi ce of
Research and Development, Cincinnati , OH 45268 , USA

Emily A. McVey Of fi ce of Pharmaceutical Science, Center for Drug Evaluation
and Research, U.S. Food and Drug Administration , Silver Spring , MD 20993 ,
USA
WIL Research, 5203DL ’s-Hertogenbosch, The Netherlands
Alejandro J. Ramirez Mass Spectrometry Center, Mass Spectrometry Core
Facility, Baylor University, Baylor Sciences Building , Waco , TX 76798 , USA
Shane Snyder Chemical and Environmental Engineering , University of Arizona ,
Tucson , AZ 85721 , USA
Jürg Oliver Straub F.Hoffmann-La Roche Ltd, Group SHE , LSM 49/2.033 ,
Basle CH-4070 , Switzerland
Kati I. Stoddard Department of Biological Sciences , University of North Texas ,
Denton , TX 76203 , USA
E. Spencer Williams Department of Environmental Science, Institute of
Biomedical Studies , Center for Reservoir and Aquatic Systems Research, Baylor
University , Waco , TX 76798-7266 , USA
1
B.W. Brooks and D.B. Huggett (eds.), Human Pharmaceuticals in the Environment:
Current and Future Perspectives, Emerging Topics in Ecotoxicology 4,
DOI 10.1007/978-1-4614-3473-3_1, © Springer Science+Business Media, LLC 2012
Background
Human interaction with the environment remains one of the most pervasive facets
of modern society. Whereas the anthropocene is characterized by rapid popula-
tion growth, unprecedented global trade and digital communications, energy
security, natural resource scarcities, climatic changes and environmental quality,
emerging diseases and public health, biodiversity and habitat modi fi cations are
routinely touted by the popular press as they canvas global political agendas and
scholarly endeavors. With a concentration of human populations in urban areas
B. W. Brooks (*)
Department of Environmental Science, Center for Reservoir and Aquatic Systems Research ,
Institute of Biomedical Studies, Baylor University , One Bear Place , #97266 ,

Waco , TX 76798 , USA
e-mail:
J. P. Berninger
Department of Environmental Science, Center for Reservoir and Aquatic Systems Research ,
Institute of Biomedical Studies, Baylor University , One Bear Place , #97266 ,
Waco , TX 76798 , USA
National Health and Environmental Effects Research Laboratory, National Research Council
Research Associates Program , Of fi ce of Research and Development, U.S. Environmental
Protection Agency , 6201 Congdon Boulevard , Duluth , MN 55804 , USA
e-mail:
A. J. Ramirez
Mass Spectrometry Center, Mass Spectrometry Core Facility , Baylor University ,
Baylor Sciences Building, One Bear Place , #97046 , Waco , TX 76798 , USA
e-mail:
D. B. Huggett
Department of Biological Sciences , University of North Texas ,
1155 Union Circle , #305220 , Denton , TX 76203 , USA
e-mail:
Perspectives on Human Pharmaceuticals
in the Environment
Bryan W. Brooks , Jason P. Berninger , Alejandro J. Ramirez ,
and Duane B. Huggett
2
B.W. Brooks et al.
unlike any other time in history, the coming decades will be de fi ned by “A New
Normal,” as proposed by Postel [ 1 ] , where the interplay among sustainable
human activities and natural resource management will inherently determine the
regional fates of human societies.
In recent years, few topics have captured the public’s attention like the pres-
ence of human pharmaceuticals in environment. Fish on Prozac [

2, 3 ] . Male fi sh
becoming female [ 4, 5 ] ? Drugs found in drinking water [ 6, 7 ] . India’s drug
problem [ 8 ] . Chances are you have seen these headlines or read related reports.
Pharmaceuticals and trace levels of other contaminants (e.g., antibacterial agents,
fl ame retardants, per fl uorinated surfactants, harmful algal toxins) are increasingly
reported in freshwater and coastal ecosystems. In the developed world, many of
these chemicals are released at very low levels (e.g., parts per trillion) from waste-
water ef fl uent discharges to surface and groundwaters. But why were citizens so
engaged by stories about fi sh on Prozac [ 3 ] and drugs in drinking water [ 7 ] ?
Because pharmacotherapy is now entrenched in everyday life, a realization that
common drugs were found in the water we drink or the fi sh we eat likely produces
a boomerang effect, where our daily reliance on well-accepted therapies was con-
cretely linked in a new way with their potential consequences to the natural world.
On an increasingly urban planet, pharmaceutical residues and traces of other
contaminants of emerging concern represent signals of the rapidly urbanizing
water cycle and harbingers of the “New Normal.”
Over the past 2 decades the implications of endocrine disruption and modula-
tion have permeated public consciousness, scienti fi c inquiry, regulatory frame-
works, and management decisions in the environmental and biomedical sciences.
Publication of Colburn, Dumanoski, and Myers’ “Our Stolen Future [ 9 ] ,” which
is often referred to as the second coming of Rachel Carson’s “Silent Spring [ 10 ] , ”
stimulated the public, scienti fi c, and regulatory attention given to endocrine dis-
ruptors and ultimately in fl uenced the environmental studies of human pharma-
ceuticals [ 11 ] . For example, human reproductive developmental perturbations
elicited by the estrogenic human pharmaceutical diethylstilbestrol and feminiza-
tion of male fi sh exposed to municipal ef fl uent discharges represent examples of
causal relationships among endocrine active substances and biologically important
adverse outcomes [ 12 ] .
In the late 1990s, research in the area of endocrine disruption was taking off,
particularly to identify constituents of ef fl uents or other environmental matrices that

were potentially responsible for endocrine perturbations in wildlife and humans.
Because many xenoestrogens are present in ef fl uent discharges, initial investiga-
tions in the UK employed toxicity identi fi cation evaluation studies to fractionate
and identify causative components of the complex mixtures inherent with ef fl uents
[
13 ] . At the same time in the USA, Arcand-Hoy et al. [ 14 ] highlighted the impor-
tance of considering human estrogen agonist and veterinary androgen agonist phar-
maceuticals as potential causative toxicants from point and nonpoint source
ef fl uents. Also in 1998, two of the fi rst review papers on pharmaceuticals in the
environment, by Halling-Sorensen et al. [ 15 ] and Ternes [ 16 ] , appeared in the litera-
ture. In 1999, another review paper, by Daughton and Ternes [ 17 ] , considered
3
Perspectives on Human Pharmaceuticals in the Environment
Pharmaceuticals and Personal Care Products (PPCP) in the environment and by
doing so coined the PPCP acronym, which remains pervasive. Subsequently, a pre-
cipitous number of workshops, symposia, special meetings, and publications related
to pharmaceuticals in the environment have occurred. For example, Fig. 1 describes
citation frequencies of just the Halling-Sorensen et al. [ 15 ] , Ternes [ 16 ] , and
Daughton and Ternes [ 17 ] papers as surrogates for the trajectory of scienti fi c inquiry
in this important area of environmental science and public health.
Some of the most important developments related to pharmaceuticals in the envi-
ronment included special issues of Toxicology Letters in 2002 and 2003, Pellston
workshops by the Society of Environmental Toxicology and Chemistry (SETAC) on
human pharmaceuticals (in 2003 [ 18 ] ) and veterinary medicines (in 2007 [ 19 ] ),
formation of the SETAC Pharmaceuticals Advisory Group (in 2005; http://www.
setac.org/node/34 ) and the Water Environment Federation’s Microconstituents
Community of Practice ( ), International Conferences on the
Occurrence, Fate, Effects, and Analysis of Emerging Contaminants in the
Environment (e.g., htpp://www.EmCon2011.com ), the International Water
Association’s MicroPol conferences (e.g., htpp://www.micropol2011.org ), and a

special issue of Environmental Toxicology and Chemistry entitled “Pharmaceuticals
and Personal Care Products in the Environment” in 2009. Following an editorial by
Brooks et al. [ 20 ] entitled “Pharmaceuticals and Personal Care Products: Research
Needs for the Next Decade,” an international workshop entitled “Effects of
Pharmaceuticals and Personal Care Products in the Environment: What are the Big
Questions?” was held by Health Canada/SETAC in April 2011 [ 21 ] . In 2012, the
SETAC Pharmaceutical Advisory Group is planning another Pellston conference on
antimicrobial resistance, which represents a major threat to global public health.
Though the information in this timely area continues to rapidly expand, it appears
Year
1998 2000 2002 2004 2006 2008 2010
Relative Cumulative Frequency of Citations
0.0
0.2
0.4
0.6
0.8
1.0
Cumulative Frequency of Citations
0
500
1000
1500
2000
2500
Fig. 1 Representative increase in peer-reviewed publications related to pharmaceuticals in the
environmental through 2010, summarized by the cumulative and relative cumulative citation
frequency of early review papers by Halling-Sorensen et al. [
15 ] , Ternes [ 16 ] , and Daughton and
Ternes [

17 ] . Citation information from Web of Knowledge

4
B.W. Brooks et al.
critically important to now consider the lessons learned from the study of human
pharmaceuticals in the environment and formulate directions for future efforts.
Environmental Analysis and Exposure
To date, the majority of information for human pharmaceuticals in the environment
is related to occurrence in various environmental matrices, which largely accounts
for publication trends summarized in Fig.
1 . Perhaps the most in fl uential paper on
occurrence was published by Kolpin et al. [ 22 ] . In 2002, this landmark article pro-
vided the fi rst national reconnaissance study of a variety of contaminants of emerg-
ing concern, including a number of pharmaceuticals, in water [ 22 ] and promises to
be the most heavily cited paper published in the history of the journal Environmental
Science & Technology . In Table 1 , we provide an overview of the representative
literature related to the environmental analysis and occurrence of pharmaceuticals
in the environment. Instead of performing an exhaustive survey and synthesis here,
we instead relay some perspectives on environmental analysis and refer readers to
the recent review of occurrence information for human pharmaceuticals by Monteiro
and Boxall [ 23 ] .
Table 1 Representative recent reviews on pharmaceutical analysis in various environmental
matrices
Target analytes Matrix Type of review
Pharmaceuticals Water Analytical methods [
64 ] , multiresidue
methods [
65 ] , LC–MS/MS methods [ 66 ] ,
basic pharmaceuticals [
67 ] , antibiotics

[
68 ] , anti-in fl ammatory drugs [ 69 ] ,
recent advances [
70 ]
Solids
a
LC–MS/MS [ 71 ] , tetracycline antibiotics [ 72 ]
Water, solids Analytical methods [
73 ] , LC–MS/MS
methods [
74 ]
Conventional and/or
contaminants of
emerging concern,
including
pharmaceuticals
Water Analytical methods [
75, 76 ]
Water, solids LC–MS in environmental analysis [
77 ]
Various environmental
matrices
Analytical methods [
78, 79 ] , methods
applied to fate [
80 ] , environmental mass
spectrometry [
81 ] , recent advances [ 82 ]
Pharmaceuticals
and/or degradation

products
Water Advanced MS techniques [
83 ] , LC–MS
methods [
84 ] , methods applied to fate
and removal [
85 ]
Various environmental
matrices
Mass spectrometry [
86 ] , analytical problems
and sample preparation [
87 ]
Other reviews related
to pharmaceutical
analysis and
general occurrence
information
Multivariate analysis [
88, 89 ] , sampling
and/or extraction [
90– 94 ] , chiral analysis
[
95 ] , general occurrence [ 23 ] , biological
tissues [
28, 29, 96 ]

a
Sediment, biosolids and soil
5

Perspectives on Human Pharmaceuticals in the Environment
Gas chromatography–mass spectrometry (GC–MS) was the primary analytical
tool used to assess the environmental occurrence of PPCPs in initial studies (Table 1 ).
The popularity of GC–MS in early work was due to its widespread availability and
historical use in contract service laboratories for historical industrial chemical
contaminants. The availability of electron-impact spectral libraries was initially
important, as they increased con fi dence in analyte identi fi cation. Further, the dis-
tinctive nonpolar operating range of GC–MS was consistent with analysis of most
personal care products (PCPs). In contrast, the use of GC–MS for analysis of phar-
maceuticals, which are relatively polar compared to most PCPs, typically requires
derivatization prior to analysis. For example, Brooks et al. [
3 ] employed GC–MS
with derivatization for initial identi fi cation of the antidepressants sertraline and
fl uoxetine in fi sh tissue. However, derivatization reactions are often unpredictable
for complex samples and can limit the quality of quantitative data. Consequently,
liquid chromatography–mass spectrometry (LC–MS) has become the technique of
choice for analyzing pharmaceuticals in environmental samples.
Numerous studies have demonstrated the distinct advantages of LC–MS for
analysis of pharmaceuticals (Table 1 ). LC–MS enables identi fi cation and
quanti fi cation without derivatization and typically results in lower detection limits
(below 1 ng/L and 1 ng/g for liquid and solid samples, respectively) and better
precision than comparable GC–MS methodologies. In environmental applications,
LC is typically combined with tandem MS (or MS/MS) to promote enhanced
selectivity and sensitivity for target analytes. In a routine MS/MS analysis, a
molecular ion is selected and subsequently fragmented to produce one or more
distinctive product ions that enable both qualitative and quantitative monitoring.
Recently introduced ultraperformance liquid chromatography (UPLC) provides a
novel approach to chromatographic separation. UPLC differs from regular LC by
the implementation of chromatographic columns with smaller particle diameters
(i.e., sub-2- m m particles), which generates elevated back pressures and narrower

chromatographic peaks. The overall effect is resolved peaks in shorter periods of
time with increased sensitivity. UPLC requires fi ttings and pumps designed to sup-
port high back pressures, which increases the price of the LC system. An important
feature of UPLC is the need of a fast detector to account for small peak widths
(ca. 10 s). In other words to acquire enough data points through chromatographic
peaks, selected mass spectrometer need to collect data points at high sampling
rates. Q-TOF mass spectrometers are often coupled with UPLC systems due to
their fast sampling rates. It is important to note, however, that LC–MS is not exempt
from limitations. One of the limitations of LC–MS is that atmospheric pressure
ionization (API) processes are in fl uenced by coextracted matrix components.
Matrix effects typically result in suppression or less frequent enhancement of ana-
lyte signal. There have been a number of methods proposed to compensate for
matrix effects, including the method of standard addition, surrogate monitoring,
and isotope dilution (Table
1 ). Although isotope dilution is the most highly recom-
mended approach for analysis of human pharmaceuticals in environmental matri-
ces, isotopically labeled standards are not always readily available for these target
analytes. A further limitation is the paucity of available isotopically labeled standards
6
B.W. Brooks et al.
for therapeutic metabolites. An alternative approach involves the use of an
appropriate internal standard (i.e., a structurally similar compound expected to
mimic the behavior of a target analyte(s)) with or without matrix-matched calibra-
tion. However, a given internal standard is typically effective over a limited reten-
tion time window. Accordingly, the use of more than one internal standard is
recommended to compensate for matrix effects throughout the chromatographic
run. Finally, it is important to point out that strategies to compensate for matrix
effects should take into account the variability of matrix within each set of samples
to be analyzed (e.g., surface water, ef fl uent, sediment, fi sh tissue).
Due to potential regulatory implications of human pharmaceuticals in the envi-

ronment, environmental analyses typically include rigorous quality assurance and
quality control (QA/QC) metrics to con fi rm reliability of analytical data. Initial
method validation provides essential performance parameters, such as method
recoveries, precision, and limits of detection (LODs). Recurring analysis of quality
control (QC) samples (e.g., method blanks, matrix spikes, laboratory control sam-
ples) is important to verify performance of the method over time, and to assess
potential matrix effects. Considering the unpredictable nature of matrix interference
in LC–MS analysis and the lack of effective strategies to deal with this dif fi culty, it
has become imperative to use QA/QC data to document and qualify analytical
results for human pharmaceuticals in environmental matrices. This is particularly
important when reporting concentrations at or near the limit of detection for a given
analytical method.
In this volume, an overview of global environmental regulatory activities rele-
vant to human pharmaceuticals is provided in Chaps.
2 and 3 . In Chap. 4 , Boxall
and Ericson examine important considerations for understanding the environmental
fate of therapeutics. Below we provide some perspectives on bioaccumulation and
effects of human pharmaceuticals in the environment.
Environmental Bioaccumulation and Effects
Though the potential for uptake of veterinary medicines by animals reared in aqua-
culture were understood for some time (see [ 24, 25 ] ), Boxall et al.’s [ 26 ] study of
the uptake of veterinary medicines from soils to plants highlighted the importance
of considering potential accumulation of human medicines in terrestrial organisms
because biosolids and ef fl uents from wastewater treatment plants can be applied
to agricultural fi elds. Such observations are particularly relevant for antibiotics.
In fact, developing an understanding of the in fl uences of human antibiotics and
antimicrobial agents on antibiotic resistance was recently identi fi ed as critical areas
of research need for environmental science and public health [ 21 ] .
In aquatic systems, Larsson et al. [ 27 ] likely provided the fi rst report of bioac-
cumulation of a human pharmaceutical, 17 a -ethinylestradiol, in bile of fi sh exposed

to Swedish ef fl uent discharges. Brooks et al.’s [ 3 ] fi ndings of the antidepressants
fl uoxetine and sertraline (and their primary metabolites) in brain, liver, and muscle
7
Perspectives on Human Pharmaceuticals in the Environment
tissues of three fi sh species from an ef fl uent-dominated stream (a.k.a. fi sh on
Prozac) appear to represent the second report in the literature of accumulation of
human pharmaceuticals in wildlife and the fi rst observation from North America.
Such observations stimulated research related to the accumulation and effects of
human pharmaceuticals in the environment and subsequently shaped the National
Pilot Study of PPCPs in Fish Tissue by the US Environmental Protection Agency
[
28 ] . This study by Ramirez et al. [ 28 ] provided the fi rst evidence of bioaccumula-
tion of a number of human pharmaceuticals in fi sh collected across a broad geo-
graphic area. A summary of research on bioaccumulation of pharmaceuticals in
aquatic organisms recently highlighted the need to understand thresholds of drug
accumulation associated with adverse effects [ 29 ] . Unfortunately, an understand-
ing of human pharmaceuticals accumulating in terrestrial wildlife is poorly under-
stood [ 20 ] but has been recently identi fi ed as a major research question [ 21 ] .
Several recent publications have started to further our understanding of the biocon-
centration/bioaccumulation potential of pharmaceuticals in a laboratory setting, as
well as publications aimed at understanding pharmaceutical metabolism in wildlife
and its role in the accumulation of drugs [ 30– 39 ] . Below we introduce important
considerations for understanding relationships between pharmaco(toxico)kinetics
and -dynamics of human medications in aquatic and terrestrial organisms. A more
thorough examination of comparative pharmacological approaches for environmental
applications is provided by Gunnarsson et al. in Chap. 5 .
Understanding the environmental risks posed by historical contaminants has
been challenged by the paucity of toxicity information available for most industrial
chemicals [ 40 ] . In the case of human pharmaceuticals, however, intensive investiga-
tions occur prior to distribution, which yields a wealth of pharmacological and toxi-

cological data compared to other industrial contaminants. To illustrate available
data, Table 2 provides a summary of common characteristics for hundreds of phar-
maceuticals. During the design of therapeutics, careful consideration is given to
target-speci fi c biomolecules (e.g., receptors, enzymes) and pathways to elicit
bene fi cial outcomes. Because side effects are not desirable and large margins of
safety (relationship between therapeutic and toxic doses) are ideal, pharmaceutical
development often results in therapeutics with relative well-understood mecha-
nisms/modes of actions (MOAs) and very low acute toxicity in mammals. For
example, a recent study predicted that less than 8% of all pharmaceuticals are
expected to be classi fi ed as highly acutely toxic to rodent models [ 41 ] . Similarly,
Berninger and Brooks [ 41 ] predicted that less than 6% of all pharmaceuticals are
acutely toxicity to fi sh below 1 mg/L.
As noted previously, concentrations of individual human pharmaceuticals in
surface water of developed countries rarely exceed parts per billion levels; thus,
limited acute toxicity is expected in surface waters of the developed world.
Unfortunately, most studies to date have only examined acute toxicity in standard
aquatic organisms [ 42 ] . However, chronic adverse responses resulting from thera-
peutic MOAs are more likely to be observed in the environment [ 41 ] , particularly
in systems with instream fl ows dominated by continuous release of ef fl uent dis-
charges [ 43 ] leading to longer effective exposure durations [ 11 ] . Early investigators
8
B.W. Brooks et al.
Table 2 A summary of the minimum and maximum values and 10th, 50th, and 90th centiles of common properties associated with pharmaceuticals
MW log P LD
50
C
max
AT R C l T
½
V

d
AqET
Min 6.94 −9.4 0.00075 7.5 × 10
−6
1.6 0.0029 0.033 0.035 8.4 × 10
−10

Centiles 10th 164 −0.95 77 0.0017 97 0.49 0.77 0.15 2.9 × 10
−5

50th 346 2.03 971 0.1300 8,127 3.71 5.01 1.03 0.0446
90th 732 5.01 12,283 9.91 681,657 27.9 32.6 6.96 69.4
Max 145,781 8.6 56,000 330 4.7 × 10
8
1,070 87,600 2,348 9.1 × 10
9

n 1,042 797 1,035 832 741 936 979 944 831
MW molecular weight (g/mol); log P octanol–water partitioning coef fi cient; LD
50
median oral lethal dose for rat model (mg/kg); C
max
human peak plasma
concentration (or therapeutic dose; m g/mL); ATR acute to therapeutic ratio margin of safety analog (LD
50
/ C
max
; see Berninger and Brooks [ 41 ] ) ; Cl clear-
ance rate (mg/min/kg); T
½

half-life of elimination (hour); V
d
apparent volume of distribution (L/kg); AqET is the aqueous effect threshold (mg/L) where
fi sh plasma BCF/ C
max
= aquatic exposure concentration at the point in which C
max
= fi sh plasma concentration and fi sh plasma BCF × exposure concentra-
tion = fi sh plasma concentration [
29 ]
9
Perspectives on Human Pharmaceuticals in the Environment
recognized the importance of leveraging mammalian pharmacological safety data
to help understand various pharmaceutical effects in the environment, because
many MOAs of human therapeutics appear to be evolutionarily conserved, particularly
in vertebrates [
14, 44– 46 ] .
In 2003, Huggett et al. [ 47 ] proposed a screening approach to identify pharma-
ceuticals in water that may result in fi sh plasma levels (or internal doses) ³ human
therapeutic levels (e.g., C
max
). Huggett’s plasma model was based on three core
assumptions: (1) Evolutionary conservation of structure and function of drug targets
among mammals and fi sh species; (2) Internal fi sh doses approaching mammalian
C
max
levels would result in similar therapeutic outcomes; and (3) A gill uptake model
[ 48 ] for predicting rainbow trout plasma concentrations following waterborne expo-
sure to nonionizable chemicals [ 48 ] . Subsequently, several recent studies have
employed the Huggett et al. plasma model approach [ 49– 51 ] or conceptually similar

variations to account for ionization in fl uences on bioavailability [ 29, 52, 53 ] . Of
particular importance, Valenti et al. [ 53 ] recently provided an independent valida-
tion of the Huggett et al. [ 47 ] plasma model when ionization of the weak base ser-
traline [ 54 ] and an alternative gill uptake model [ 48 ] was considered. Valenti et al.
[ 53 ] also employed an adverse outcome pathway (AOP) design [ 55 ] , which included
quanti fi cation of binding at the therapeutic target and anxiety-related behavioral
responses stereotypical of the therapeutic ef fi cacy of this model antidepressant. In
the Valenti et al. [ 53 ] study, adult male fathead minnow were exposed via aqueous
exposure to sertraline for 21 days. Fish plasma concentrations were accurately pre-
dicted from water exposures when pH in fl uences on ionization and lipophilicity
were considered [ 29, 52, 54 ] . When these plasma levels in fi sh exceeded the human
therapeutic dose ( C
max
) of sertraline, binding to the serotonin reuptake transporter
and antianxiety behavior were signi fi cantly affected [ 53 ] . The AOP approach was
recently proposed by Ankley et al. [ 55 ] for linking molecular initiation events, such
as those related to pharmaceutical interactions with a target site (e.g., a receptor),
with cascading events leading to adverse outcomes at the individual and population
level, which can be used as measures of effect in risk assessments. As demonstrated
by Valenti et al. [ 53 ] , linking predictions of uptake from surface waters to fi sh
plasma with conceptual AOP models appear to represent a sound foundation from
which potentially hazardous human pharmaceuticals may be identi fi ed.
Probabilistic hazard assessment approaches, which are commonly used to sup-
port environmental and public health decision making, can use existing mammalian
pharmacological safety data to develop predictive models for various parameters
[ 41 ] . These predictive tools can support prioritization activities for testing hypoth-
eses regarding pharmacological parameters of various drug classes or chemical
speci fi c computational attributes that may result in hazards to wildlife [
41 ] . For
example, Table 2 presents the minimum and maximum values and 10th, 50th and

90th centiles of probabilistic pharmaceutical distributions (PPD) of molecular
weight, logP, acute LD
50
, C
max
, acute to therapeutic ratio margin of safety analog
(LD
50
/ C
max
; see [ 41 ] ), clearance rate, half-life of elimination, apparent volume of
distribution ( V
d
), and the aqueous effect threshold (AqET; see [ 52 ] ) based on data
from hundreds of pharmaceuticals. PPD approaches can be used to predict the
10
B.W. Brooks et al.
likelihood of encountering another therapeutic with attributes of interest. To illus-
trate the utility of PPD analyses, Fig. 2 depicts a PPD for V
d
. Brie fl y, V
d
data were
ranked and converted to probability percentages then plotted against respective
probability ranks on a log-probability scale; centiles were determined by regression
(see [ 30 ] for a complete description of methods). Using this approach, we predict
that 10% or less of all pharmaceuticals would have V
d
values of 0.15 L/kg. In Fig. 3 ,
we extend the PPD assessment to predict the likelihood of encountering a pharma-

ceutical in surface waters exceeding the AqET value, which is based here on the
speci fi c assumptions of Huggett et al.’s [ 47 ] plasma model. For example, 10% of all
pharmaceuticals are predicted to result in internal fi sh plasma concentrations equal-
ing the human C
max
value at or below an environmentally relevant surface water
concentration of 29 ng/L (Fig. 3 , Table 2 ).
Based on the current state of the science, it appears critical to develop an advanced
understanding of the risks associated with human pharmaceuticals in the environ-
ment. In Chaps. 6 and 7 , Lattier et al. consider mechanistic characteristics of drugs
for reconstructing environmental exposure scenarios and Brain and Brooks provide
perspectives for incorporating non-standard endpoints in environmental risk assess-
ments, respectively. In Chap. 8 , Williams and Brooks examine human health risk
assessment considerations for environmental exposures to therapeutics. When the
outcome of an environmental risk assessment identi fi es unacceptable risks to wildlife
or humans, risk management decisions and practices serve as interventions to
protect public health and the environment. In the case of pharmaceuticals and other
Apparent Volume of Distribution (L/kg)
10
-3
10
-2
10
-1
10
0
10
1
10
2

10
3
10
4
Percent Rank
0.01
0.1
1
10
30
50
70
90
99
99.9
99.99
Fig. 2 Probabilistic pharmaceutical distribution of apparent volume of distribution (L/kg) for 944
pharmaceuticals. Reference lines relate to the 10th, 50th and 90th centiles (Table
2 ), which corre-
spond to 0.15, 1.03, and 6.96 L/kg, respectively. For example, apparent volume of distribution is
predicted by this model to be at or above 6.96 L/kg for 10% of all pharmaceuticals

11
Perspectives on Human Pharmaceuticals in the Environment
contaminants in treated wastewater ef fl uents, a number of treatment approaches,
including appropriately designed and maintained constructed wetlands [ 56 ] , appear
viable for supporting risk management of indirect and direct potable water reuse.
In this volume, Chaps. 9 and 10 examine timely issues related to environmental risk
management. In Chap. 9 , Gerrity and Snyder examine the available information
related to the ef fi cacy of various wastewater and drinking water treatment technolo-

gies for human pharmaceuticals. In Chap. 10 , Stoddard and Huggett conclude this
volume with an interesting perspective on pharmaceutical take back programs,
which promise to divert unused medications from down the drain discharges and
drug abuse by and poisonings of unintended users.
Lessons learned from human pharmaceuticals in the environment will continue to
advance our understanding of the environmental risks of chemicals. For example, a
number of organic contaminants are chiral, which remains an important environmental
consideration because fate and effects often differ among enantiomers [ 57 ] . Herein,
studies of chiral pharmaceuticals have advanced our understanding of risks posed by
other chiral chemicals [ 58 ] . Similarly, many environmental contaminants, including
metabolites and degradates, are weak acids and weak bases. Because site-speci fi c pH
in fl uences environmental fate, uptake and toxicity, the study of ionizable therapeutics
(~70% of all drugs are weak bases) has advanced our understandings of the impacts of
climatic changes on bioaccumulation and toxicity of moderately polar and ionizable
chemicals [ 59, 60 ] . Interestingly, lessons learned from the study and design of less-toxic
Aqueous Effect Threshold (mg/L)
10
-11
10
-9
10
-7
10
-5
10
-3
10
-1
10
1

10
3
10
5
10
7
10
9
Percent Rank
0.01
0.1
1
10
30
50
70
90
99
99.9
99.99
Fig. 3 Probabilistic pharmaceutical distribution of aqueous effect threshold (AqET; mg/L) for 831
pharmaceuticals. Reference lines relate to the 10th, 50th, and 90th centiles (Table
2 ), which cor-
respond to 29 ng/L, 44.6 m g/L, and 66.4 mg/L, respectively. For example, an aquatic concentration
leading to a plasma concentration in fi sh above the mammalian C
max
value is predicted by the
AqET model to be at or below 29 ng/L for 10% of all pharmaceuticals

12

B.W. Brooks et al.
pharmaceuticals, often described as benign by design [ 61 ] , can be extended to advance
green chemistry principles by developing sustainable molecular design guidelines for
reducing the toxicity of other industrial contaminants [ 62, 63 ] . To the fi elds of aquatic
toxicology and environmental risk assessment in particular, understanding the toxicity
of human pharmaceuticals in the environment is beginning to advance our understand-
ing of toxicity pathways. To date, relatively few toxicity pathways have been de fi ned in
ecological systems, but hundreds of pharmaceuticals targets are evolutionarily con-
served across the various kingdoms. Developing an understanding of pharmaceutical
MOAs and associated AOPs will improve prospective and retrospective diagnosis and
management of environmental risks posed by industrial contaminants. Clearly a num-
ber of timely research questions remain unanswered [
21 ] .
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42. Brausch JM, Connors KA, Brooks BW, Rand GM (2012) Human pharmaceuticals in the
aquatic environment: a critical review of recent toxicological studies and considerations for
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43. Brooks BW, Riley TM, Taylor RD (2006) Water quality of ef fl uent-dominated stream ecosys-
tems: ecotoxicological, hydrological, and management considerations. Hydrobiologia
556:365–379
44. Seiler JP (2002) Pharmacodynamic activity of drugs and ecotoxicology: can the two be con-
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45. Huggett DB, Brooks BW, Peterson B, Foran CM, Schlenk D (2002) Toxicity of select beta-
adrenergic receptor blocking pharmaceuticals ( b -blockers) on aquatic organisms. Arch Environ
Contamin Toxicol 42:229–235
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La Point TW (2003) Aquatic ecotoxicology of fl uoxetine. Toxicol Lett 142:169–183
47. Huggett DB, Cook JC, Ericson JF, Williams RT (2003) A theoretical model for utilizing mammalian
pharmacology and safety data to prioritize potential impacts of human pharmaceuticals to fi sh.
Hum Ecol Risk Assess 9:1789–1799
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elimination of superhydrophobic organic compounds by rainbow trout ( Oncorhynchus mykiss ).
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pharmaceuticals from sewage ef fl uents into fi sh blood plasma. Environ Toxicol Pharmacol
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levels of levonorgestrel detected in blood plasma of fi sh: results from screening rainbow trout
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centrations for 500 pharmaceuticals. Regul Toxicol Pharmacol 58:516–523

52. Berninger JP, Du B, Connors KA, Eytcheson SA, Kolkmeier MA, Prosser KN, Valenti TW,
Chambliss CK, Brooks BW (2011) Effects of the antihistamine diphenhydramine to select
aquatic organisms. Environ Toxicol Chem 30:2065–2072
53. Valenti TV, Gould GG, Berninger JP, Connors KA, Keele NB, Prosser KN, Brooks BW (2012)
Human therapeutic plasma levels of the selective serotonin reuptake inhibitor (SSRI) sertraline
decrease serotonin reuptake transporter binding and shelter seeking behavior in adult male
fathead minnows. Environ Sci Technol 46:2427–2435
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28:2685–2694
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outcome pathways: a conceptual framework to support ecotoxicology research and risk assess-
ment. Environ Toxicol Chem 29:730–741
15
Perspectives on Human Pharmaceuticals in the Environment
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phosphorus on diel pH in wadeable streams: implications for ecological risk assessment of
ionizable contaminants. Integr Environ Assess Manag 7:636–647
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(2011) In fl uence of Climate change on reservoir water quality assessment and management:
effects of reduced in fl ows on diel pH and site-speci fi c contaminant hazards. In: Linkov I,
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aquatic toxicity. Green Chem 13:2373–2379
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2
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16
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17
B.W. Brooks and D.B. Huggett (eds.), Human Pharmaceuticals in the Environment:
Current and Future Perspectives, Emerging Topics in Ecotoxicology 4,
DOI 10.1007/978-1-4614-3473-3_2, © Springer Science+Business Media, LLC 2012
Introduction
An overview is given on environmental risk assessment for pharmaceuticals (ERA),
with a description of the current regulatory requirements for human pharmaceuti-
cals ERA in Europe and the USA as well as developments worldwide. In addition,
further developments on national levels concerning the environmental safety of
pharmaceuticals are presented. Also, a short comparison with international veteri-
nary pharmaceuticals guidelines and with biocides ERA is given.
As long as human population density is low and excreta are spread diffusely over
a large area, no signi fi cant levels of PAS or metabolites are expected in the environ-
ment. But when population density increases, when excreta collect in sewage and
the latter is discharged, after wastewater treatment or not, to receiving waters, mea-
surable to signi fi cant concentrations in surface waters may be reached. With strong
population growth in industrialised societies from the nineteenth century onward,
with sewage collection systems in the growing cities and with the increase in the
number of pharmaceutical companies and their biologically active products, a rise
in environmental concentrations of at least certain PAS followed during the past
century. A parallel development in analytical methods and power, expressed as
constantly decreasing limits of detection and quantitation, inevitably led to determi-
nations of PAS in environmental matrices.
J. O. Straub (*)
F.Hoffmann-La Roche Ltd, Group SHE ,
LSM 49/2.033 , Basle CH-4070, Switzerland
e-mail:

T. H. Hutchinson
CEFAS Weymouth Laboratory , Centre for Environment, Fisheries and Aquaculture Sciences ,
The Nothe, Barrack Road , Weymouth , Dorset DT4 8UB , UK
e-mail:
Environmental Risk Assessment for Human
Pharmaceuticals: The Current State
of International Regulations
Jürg Oliver Straub and Thomas H. Hutchinson